The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament which particularly acts on the central nervous system.
Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. A number of pharmacological and genetic experiments involving receptors for serotonin strongly implicate the 5-HT2c receptor subtype in the regulation of food intake (Obes. Res. 1995, 3, Suppl. 4, 449S-462S). The 5-HT2c receptor subtype is transcribed and expressed in hypothalamic structures associated with appetite regulation. It has been demonstrated that the 5-HT2c receptor agonist m-chlorophenylpiperazine (mCPP), which has some preference for the 5-HT2c receptor, reduces food intake in mice that express the normal 5-HT2c receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2c receptor (Nature 1995, 374, 542-546). In a recent clinical study, a slight but sustained reduction in body weight was obtained after 2 weeks of treatment with mCPP in obese subjects (Psychopharmacology 1997, 133, 309-312). Recently, a series of pyrrolo[3,2,1-ij]quinoline derivatives was identified to be 5-HT2c receptor agonists having selectivity over the 5-HT2A receptor (Isaac M., et al., Bioorg. Med. Chem. Lett. 2000, 10, 919-921). The compounds are said to offer a novel approach to the treatment of obesity and epilepsy.
Weight reduction has also been reported from clinical studies with other xe2x80x9cserotonergicxe2x80x9d agents (see e.g. IDrugs 1998, 1, 456-470). For example, the 5-HT reuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptake inhibitor dexfenfluramine have exhibited weight reduction in controlled studies. However, currently available drugs that increase serotonergic transmission appear to have only a moderate and, in some cases, transient effects on the body weight.
The 5-HT2c receptor subtype has also been suggested to be involved in CNS disorders such as depression and anxiety (Exp. Opin. Invest. Drugs 1998, 7, 1587-1599; IDrugs, 1999, 2, 109-120).
The 5-HT2c receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (IDrugs, 1999, 2, 109-120).
Compounds which have a selective effect on the 5-HT2c receptor may therefore have a therapeutic potential in the treatment of disorders like those mentioned above. Of course, selectivity also reduces the potential for adverse effects mediated by other serotonin receptors.
U.S. Pat. No. 3,253,989 discloses the use of mCPP as an anorectic agent.
EP-A1-863 136 discloses azetidine and pyrrolidine derivatives which are selective 5-HT2c receptor agonists having antidepressant activity and which can be used for treating or preventing serotonin-related diseases, including eating disorders and anxiety.
EP-A1-330 263 discloses piperazinylalkylpyrimidines as hypoglycemic agents.
WO 87/04928 discloses 2-(1-piperazinyl)pyrimidines as agents for treating neuropathy.
EP-A2-226842 discloses 1,4-naphthalenedione heterocyclic derivatives as antiallergics and antiasthmatics including 2-(3-bromophenyl)-4-(1-piperazinyl)-pyrimidine.
EP-A-657 426 discloses tricyclic pyrrole derivatives having activity on the 5-HT2c receptor and which inter alia may be used for treating eating disorders.
EP-A-655 440 discloses 1-aminoethylindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
EP-A-572 863 discloses pyrazinoindoles having activity on the 5-HT2c receptor and which may be used for treating eating disorders.
J. Med. Chem. 1978, 21, 536-542 and U.S. Pat. No. 4,081,542 disclose a series of piperazinylpyrazines having central serotonin-mimetic activity.
U.S. Pat. No. 4,078,063 discloses a series of piperazinylpyridines having anorexic activity.
J. Med. Chem. 1981, 24, 93-101 discloses a series of piperazinylquinoxalines with central serotoninmimetic activity.
ES 514549 discloses piperazine derivative with anorexigenic action.
EP 370560 discloses 1-[mono- or bis(trifluoromethyl)-2-pyridinyl]piperazines as central nervous system agents.
J. Med. Chem. 1987, 30, 1794-1798 discloses 2-(4-heterocyclylpiperazin-1-yl) derivatives including 2-phenoxy-4-piperazin-1-ylpyrimidine.
DE 2202385 discloses antimicrobial (5-nitro-2-furyl)pyrimidines and -thiadiazoles including 2-(5-nitro-2-furyl)-4-(4-methyl-1-piperazinyl)pyrimidine and 2-(5-nitro-2-furyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]pyrimidine.
J. Med Chem. 1987, 30, 1210-1214 discloses N,N-disubstituted 6-alkoxy-2-pyridinamines as anticonvulsant agents including 1-(6-methoxy-2-pyridinyl)piperazine, 1-(6-ethoxy-2-pyridinyl)piperazine, 1-(6-isopropoxy-2-pyridinyl)piperazine, 1-(6-isobutoxy-2-pyridinyl)piperazine, 1-(6-cyclopropylmethoxy-2-pyridinyl)piperazine, 1-(6-cyclohexylmethoxy-2-pyridinyl)piperazine, and 1-(6-cyclohexyloxy-2-pyridinyl)piperazine.
J. Med. Chem. 1989, 32, 1237-1242 discloses 6-alkyl-N,N-disubstituted-2-pyridinamines as anticonvulsant agents including 1-(6-butylthio-2-pyridinyl)piperazine, 1-(6-cyclohexylmethyl-2-pyridinyl)piperazine and 1-[6-(2-phenylethyl)-2-pyridinyl]piperazine.
JP 07300474 discloses drugs for treatment of diseases related to serotoninergic nerve including 1-(6-phenoxy-2-pyridinyl)piperazine and 1-[6-(substituted)phenoxy-2-pyridinyl]piperazines, 1-(6-benzyloxy-2-pyridinyl)piperazine, 1-(6-cyclobutyloxy-2-pyridinyl)piperazine, and 1-(6-cyclopentyloxy-2-pyridinyl)piperazine
EP 580465 discloses heterocyclic piperazines as 5-HT3 agonists including 6-chloro-2-(3-methylpiperazinyl)pyridine and 6-chloro-2-(4-methylpiperazinyl)pyridine.
WO 00/12475 discloses indoline derivatives as 5-HT2b and/or 5-HT2c receptor ligands, especially for the treatment of obesity.
WO 00/12510 discloses pyrroloindoles, pyridoindoles and azepinoindoles as 5-HT2c receptor agonists, particularly for the treatment of obesity.
WO 00/12482 discloses indazole derivatives as selective, directly active 5-HT2c receptor ligands, preferably 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/12502 discloses pyrroloquinolines as 5-HT2c receptor agonists, particularly for use as anti-obesity agents.
WO 00/35922 discloses 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)ones as 5HT2c agonists, which may be used for the treatment of obesity.
WO 00/44737 discloses aminoalkylbenzofurans as 5-HT2c agonists, which may be used for the treatment of obesity.
Further compounds reported to be 5HT2c receptor agonists are, for example, indazolylpropylamines of the type described in WO 00/12481; indazoles of the type described in WO 00/17170; piperazinylpyrazines of the type described in WO 00/76984; heterocycle fused xcex3-carbolines of the type described in WO 00/77001, WO 00/77002 and WO 00/77010; benzofurylpiperazines of the type described in WO 01/09111 and WO 01/09123; benzofurans of the type described in WO 01/09122; benzothiophenes of the type described in 01/09126; aminoalkylindazoles of the type described in WO 98/30548; indoles of the type described in WO 01/12603; indolines of the type described in WO 01/12602; pyrazino(aza)indoles of the type described in WO 00/44753 and tricyclic pyrroles or pyrazoles of the type described in WO 98/56768.
WO 96/11920 discloses CNS-active pyridinylurea derivatives.
WO 95/01976 discloses indoline derivatives active as 5-HT2c antagonists and of potential use in the treatment of CNS disorders.
WO 99/58490 disloses aryl-hydronaphthalen-alkanamines which may effectuate partial or complete blockage of serotonergic 5-HT2c receptors in an organism.
According to the invention novel compounds of the general formula (I) are provided: 
wherein
(i) X and Y represent both nitrogen and Z represents CH, forming a pyrazine derivative, or
(ii) X and Z represent both CH and Y represents nitrogen, forming a pyridine derivative, or
(iii) X represents C-CF3, Z represents CH, and Y represents nitrogen, forming a 4-trifluoromethylpyridine derivative, or
(iv) Y and Z represent both nitrogen and X represents CH, forming a pyrimidine derivative, and wherein
R1 and R2 are each, independently, selected from a group A, consisting of 
xe2x80x83or from a group B, consisting of aryl-C1-C6-alkyl, aryl-C1-C6-alkoxy, heteroaryl-C1-C6-alkoxy, aryloxy-C2-C6-alkoxy, heteroaryloxy-C2-C6-alkoxy, 1-indanyloxy, 2-indanyloxy, aryloxy, heteroaryloxy, arylthio, heteroarylthio, C5-C6-cycloalkylthio, C5-C8-alkoxy, C5-C8-alkylthio, C3-C6-alkynyloxy, C3-C6-alkenyloxy, fluoro-C2-C4-alkoxy, C4-C8-cycloalkyloxy, C3-C8-cycloalkyl-C1-C4-alkoxy, halogen, aryl-C1-C4-alkylthio, heteroaryl-C1-C4-alkylthio, aryl-C1-C4-alkylamino, heteroaryl-C1-C4-alkylamino, heteroaryl and aryl;
with the proviso that:
(i) R1 and R2 are different and are not both selected from group A or group B at the same time;
(ii) when formula (I) is a pyrazine derivative R1 or R2 are other than, phenylthio, phenylmethylthio, phenyl or phenyl substituted by halogen;
(iii) R1 in formula (I) is halogen, especially chloro, only when (I) is a pyrazine derivative and when R2 simultaneously is 2-methylpiperazin-1-yl, 2-ethylpiperazin-1-yl or trans-2,5-dimethylpiperazin-1-yl;
(iv) when formula (I) is a pyrazine derivative and R1 is 4-piperidinyloxy, R2 is other than 3-pyridinylmethoxy, 4-quinolinylmethoxy, 2,4-dimethoxybenzyloxy and 3-(4-pyridinyl)propoxy;
(v) when both X and Z are CH and Y is N in formula (I), forming a pyridine derivative, and R1 is 1-piperazinyl or 4-methylpiperazin-1-yl, then R2 is other than, 2-phenylethyl, benzyloxy, benzylamino, phenylthio, phenoxy, substituted phenoxy, C4-C8-cycloalkyloxy and C3-C8-cycloalkylmethoxy;
(vi) when X is CH and Z and Y both are nitrogen in formula (I), forming a pyrimidine derivative, and R2 is 1-piperazinyl, then R1 is other than phenoxy, phenyl or phenyl substituted by bromo, and C5-C8 alkoxy; and when R2 is 4-methylpiperazin-1-yl or 4-(2-hydroxyethyl)piperazin-1-yl, then R1 is other than 5-nitro-2-furyl;
(vii) when X is CH and Z and Y both are nitrogen in formula (I), forming a pyrimidine derivative, and R1 is 1-piperazinyl, then R2 is other than C5-C8 alkoxy;
and where
R3 is H or C1-4-alkyl, allyl, 2-hydroxyethyl, or 2-cyanoethyl, or a nitrogen protecting group, or a prodrug moiety such as an acyl- or an alkoxycarbonyl group forming a cleavable amide or carbamate linkage;
R3 is preferably hydrogen;
R4 is hydrogen or C1-4 alkyl, preferably hydrogen, methyl or ethyl, more preferably hydrogen or methyl;
and wherein any aryl or heteroaryl residue, alone or as part of another group, in R1 or R2 may be independently substituted in one or more positions, preferably one or two, by C1-4 alkyl, C1-4-alkoxy, C1-4-alkylthio, C2-4-acyl, C1-4-alkylsulphonyl, cyano, nitro, hydroxy, C2-6-alkenyl, C2-6-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, xe2x80x94N(R5)(R6), aryl, aryloxy, arylthio, aryl-C1-4-alkyl, aryl-C2-4-alkenyl, aryl-C2-4-alkynyl, heteroaryl, heteroaryloxy, heteroarylthio or heteroaryl-C1-4-alkyl, aryl-C1-4-alkoxy, aryloxy-C1-4-alkyl, dimethylamino-C2-4-alkoxy;
and wherein any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in R1 or R2 in turn may be substituted in one or more positions, preferably one, independently of each other by C1-4-alkyl, C1-4-alkoxy, halogen, trifluoromethyl, cyano, hydroxy or dimethylamino; and
R5 and R6 independently of each other are hydrogen, methyl or ethyl, or together with the nitrogen atom to which they are bound form a pyrrolidine, piperazine, morpholine, thiomorpholine or a piperidine ring;
and pharmaceutically acceptable salts, hydrates, geometrical isomers, tautomers, optical isomers, N-oxides and prodrug forms thereof.
When R3 serves as a nitrogen protecting group R3 is t-butoxycarbonyl (t-BOC), benzyl or trityl.
In case the compounds of formula (I) can be in the form of optical isomers, the invention comprises the racemic mixture as well as the individual enantiomers as such.
In case the compounds of formula (I) contain groups, which may exist in tautomeric forms, the invention comprises the tautomeric forms of the compounds as well as mixtures thereof.
In case the compounds of formula (I) can be in the form of geometrical isomers, the invention comprises the geometrical isomers as well as mixtures thereof.
According to another aspect, the invention provides the compounds according to formula (I) above for use in therapy.
Still another aspect of the invention provides a pharmaceutical composition comprising a compound according to formula (I) above as the active ingredient, preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.
In yet another aspect, the invention provides a method for the treatment of a human or animal subject suffering from a serotonin-related disease, particularly 5-HT2c receptor-related, especially eating disorders, particularly obesity; memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy, and urinary disorders.
Another aspect of the invention provides for the use of the compounds according to formula (I) above for the manufacture of a medicament for the treatment of a serotonin-related disease, particularly 5-HT2c receptor-related, especially eating disorders, particularly obesity; memory disorders; schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy and urinary disorders.
Finally a method for modulating 5HT2c receptor function is an aspect of the invention.
According to the present invention, a class of novel compounds has been developed which compounds bind to the 5-HT2c receptor (agonists and antagonists) and which therefore may be used for the treatment of serotonin-related disorders.
First, the various terms used, separately and in combinations, in the above definition of the compounds having the general formula (I) will be explained.
By xe2x80x9cheteroatomxe2x80x9d is meant nitrogen, oxygen, sulphur, and in heterocyclic rings (including heteroaromatic as well as saturated and partially saturated heterocyclic rings), also selenium.
The term xe2x80x9carylxe2x80x9d is intended to include aromatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthyl (can be linked to the remainder of the molecule via a carbon atom in any ring) and indanyl (can be linked to the remainder of the molecule via a carbon atom in any ring).
The term xe2x80x9cheteroarylxe2x80x9d means a mono- or bicyclic aromatic ring system, only one ring need be aromatic, and which can be linked to the remainder of the molecule via a carbon or nitrogen atom in any ring, and having from 5 to 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur, oxygen and selenium. Examples of such heteroaryl rings are pyrrole, imidazole, thiophene, furan, thiazole, isothiazole, thiadiazole, oxazole, isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, tetrazole, chroman, isochroman, coumarin, quinoline, quinoxaline, isoquinoline, phthalazine, cinnoline, quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene, benzofuran, 2,3-dihydrobenzofuran, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole, benzothiazole, 2,1,3-benzothiadiazole, 2,1,3-benzoselenadiazole, benzimidazole, indazole, 2,3-dihydro-1,4-benzodioxine, 1,3-benzodioxole, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, 1,5-naphthyridine, 1,8-naphthyridine, 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine, and 2,3-dihydro-1,4-benzoxathiine. If a bicyclic aryl or heteroaryl ring is substituted, it may be substituted in any ring.
Exemplary aryl-C1-C6-alkyl, in which the alkyl portion of the group may be straight or branched, include benzyl, 2-phenylethyl, 3-phenyl-1-propyl, 1-phenylethyl, 1-phenyl-2-propyl and the like.
Exemplary aryl-C1-C6-alkoxy, in which the alkyl portion of the group may be straight or branched, include benzyloxy, 2-naphthylmethoxy, 2-phenylethoxy, 3-phenyl-1-propoxy, 1-phenylethoxy, 1-phenyl-2-propoxy, 2-phenyl-1-propoxy and the like.
Exemplary aryloxy-C2-C6-alkoxy, in which the alkyl portion of the group may be straight or branched, include 2-phenoxyethoxy, 2-(1-naphthyloxy)ethoxy, 3-(2-naphthyloxy)-1-propoxy, 3-phenoxy-1-propoxy, 4-phenoxy-1-butoxy, 5-phenoxy-1-pentoxy, 1-phenoxy-2-propoxy and the like.
Exemplary C3-C8-cycloalkyl-C1-C4-alkoxy, in which the alkyl portion of the group may be straight or branched, include cyclopropylmethoxy, cyclopentylmethoxy, 2-cyclohexylethoxy, 1-cyclohexylethoxy, 1-cyclopropylethoxy, 1-cyclobutylethoxy and the like.
Exemplary heteroaryl-C1-C4-alkylamino include 2-(2-pyridinyl)ethylamino, 3-pyridinylmethylamino, 2-(2-thienyl)ethylamino, 2-(1H-indol-3-yl)ethylamino and the like.
Exemplary heteroaryloxy-C2-C6-alkoxy include 2-(8-quinolinyloxy)ethoxy, 2-(3-pyridinyloxy)ethoxy, 3-(8-quinolinyloxy)propoxy and the like
Exemplary C3-C6-alkynyloxy include propargyloxy, 1-hexynyloxy, 2-hexynyloxy, 3-butynyloxy, 3-pentynyloxy and the like.
C5-8-alkoxy may be straight or branched. Exemplary alkoxy groups include pentyloxy, isopentyloxy, hexyloxy, and isohexyloxy.
Halogen includes fluorine, chlorine or bromine.
Where it is stated above that aryl and heteroaryl residues may be substituted (in one or more postions), this applies to aryl and heteroaryl per se as well as to any combined groups containing aryl or heteroaryl residues, such as heteroaryloxy-C2-C6-alkoxy, heteroaryloxy, aryl-C1-C6-alkoxy etc.
The term xe2x80x9cN-oxidesxe2x80x9d means that one or more nitrogen atoms, when present in a compound, are in N-oxide form (Nxe2x86x92O).
The term xe2x80x9cprodrug formsxe2x80x9d means a pharmacologically acceptable derivative, such as a carbamate or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman""s, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with organic and inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, toluenesulphonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
Preferred embodiments of the invention are:
a compound of formula (I) wherein X and Y represent both nitrogen and Z represents CH, forming a pyrazine derivative;
a compound of formula (I) wherein Y and Z both represent nitrogen and X represents CH, forming a pyrimidine derivative;
a compound of formula (I) wherein R1 or R2 is selected from 
xe2x80x83and wherein R3 is hydrogen;
a compound of formula (I) wherein R1 or R2 is selected from 
xe2x80x83and where R3 is hydrogen and R4 is selected from hydrogen or methyl or ethyl;
a compound of formula (I) wherein R1 or R2 is 
xe2x80x83and where R3 is hydrogen and R4 is selected from hydrogen or methyl or ethyl; and
a compound of formula (I) wherein R1 or R2 is selected from 
In a further preferred embodiment, the compounds of formula (I) are selected from compounds in which X and Y both are nitrogen and Z is CH giving pyrazine derivatives of formula (II): 
wherein
R2 and R3 are as defined above wherein any aryl and heteroaryl residue, alone or as part of another group, in R2 in turn may be substituted in one or more positions, preferably one or two, independently of each other by C1-4-alkyl, C1-4-alkoxy, C1-4-alkylthio, C2-4-acyl, C1-4-alkylsulphonyl, cyano, nitro, hydroxy, C2-6-alkenyl, C2-6-alkynyl, fluoromethyl, trifluoromethyl, trifluoromethoxy, halogen, xe2x80x94N(R5)(R6), aryl, aryloxy, arylthio, aryl-C1-4-alkyl, aryl-C2-4-alkenyl, aryl-C2-4-alkynyl, heteroaryl, heteroaryloxy, heteroarylthio or heteroaryl-C1-4-alkyl, aryl-C1-4-alkoxy, aryloxy-C1-4-alkyl, dimethylamino-C2-4-alkoxy;
wherein any aryl or heteroaryl residue as substituents on aryl or heteroaryl, alone or as part of another group, in R2 in turn may be substituted in one or more postions, preferably one, independently of each other by C1-4-alkyl, C1-4-alkoxy, halogen, trifluoromethyl, cyano, hydroxy or dimethylamino; R5 and R6 are as defined above; and
R7 is hydrogen or C1-4 alkyl.
Another aspect of the invention is a compound of any of the formulae herein wherein R3 is hydrogen; or wherein R7 is hydrogen, methyl, or ethyl; or wherein R7 is methyl and is attached to the C2-position of the piperazine ring; or wherein R7 is hydrogen.
In formula (II), R3 is preferably hydrogen, and R7 is preferably hydrogen or C1-4-alkyl. When R7 is C1-4-alkyl, it is most preferably substituted in the 2-postion of the piperazine ring. R7 is most preferably hydrogen or methyl.
Preferred compounds of the general formula (I) above are:
2-(Benzyloxy)-6-(1-piperazinyl)pyrazine,
2-[(2-Methoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-[(3-Methoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-[(3,5-Difluorobenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-(1-Naphthylmethoxy)-6-(1-piperazinyl)pyrazine,
2-(1-Phenylethoxy)-6-(1-piperazinyl)pyrazine,
2-[1-(3-Fluorophenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[1-(2-Methoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-(3,4-Dihydro-2H-chromen-4-yloxy)-6-(1-piperazinyl)pyrazine,
2-(2-Phenylethoxy)-6-(1-piperazinyl)pyrazine,
2-[(2-Phenoxybenzyl)oxy]-6-(-piperazinyl)pyrazine,
2-[2-(3-Chlorophenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(2-Methoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(3-Methoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(4-Methoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(2,5-Dimethoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[(2-Phenylethyl)sulfanyl]-6-(1-piperazinyl)pyrazine,
2-[(5-Fluoro-2-methoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-[(3-Cyanobenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-[(2-Chlorobenzyl)sulfanyl]-6-(1-piperazinyl)pyrazine,
2-[2-(4-Dimethylaminophenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(1H-Indol-3-yl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(1H-Indol-1-yl)ethoxy]-6-(1-piperazinyl)pyrazine,
4-(Benzyloxy)-2-(1-piperazinyl)pyrimidine,
4-[(2-Methoxybenzyl)oxy]-2-(1-piperazinyl)pyrimidine,
2-{[3-(Benzyloxy)benzyl]oxy}-4-(1-piperazinyl)pyrimidine,
2-Benzyl-6-(1-piperazinyl)pyrazine,
2-[(3,5-Dimethoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
1-[6-(Benzyloxy)-2-pyrazinyl]-2-methylpiperazine,
1-[6-(Benzyloxy)-2-pyrazinyl]-2-ethylpiperazine
1-[6-(Benzyloxy)-2-pyrazinyl]-trans-2,5-dimethylpiperazine.
2-[2-(2-Fluorophenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-(2,3-Dihydro-1H-inden-1-ylmethoxy)-6-(1-piperazinyl)pyrazine
2-(4-Phenoxybutoxy)-6-(1-piperazinyl)pyrazine.
2-[(5-Phenoxypentyl)oxy]-6-(1-piperazinyl)pyrazine.
2-[(2,5-Dimethoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine.
2-{[2-(2-Phenylethyl)benzyl]oxy}-6-(1-piperazinyl)pyrazine
(2R)-1-[6-(Benzyloxy)-2-pyrazinyl]-2-methylpiperazine,
2-[2-(2,6-Difluorophenoxy)ethoxy]-6-(1-piperazinyl)pyrazine
2-[2-(2-Naphthyloxy)ethoxy]-6-(1-piperazinyl)pyrazine
2-(1-Methyl-2-phenylethoxy)-6-(1-piperazinyl)pyrazine
2-{[2-(Phenoxymethyl)benzyl]oxy}-6-(1-piperazinyl)pyrazine
2-[(5-Fluoro-2-methoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine
2-[(2,5-Difluorobenzyl)oxy]-6-(1-piperazinyl)pyrazine
2-[(2-Fluorobenzyl)oxy]-6-(1-piperazinyl)pyrazine
2-(Benzo[b]thiophen-3-ylmethoxy)-6-(1-piperazinyl)pyrazine,
2-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-6-(1-piperazinyl)pyrazine,
2-[1-(2,6-Difluoro-phenyl)-ethoxy]-6-(1-piperazinyl)pyrazine,
2-(2-Naphthalen-2-yl-ethoxy)-6-(1-piperazinyl)pyrazine,
2-[3-(Naphthalen-2-yloxy)-propoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(7-Methoxy-naphthalen-2-yloxy)-ethoxy]-6-(1-piperazinyl)pyrazine,
2-[5-(4-Chlorophenyl)-2-methylfuran-3-ylmethoxy]-6-(1-piperazinyl)pyrazine,
2-(1H-Indol-4-ylmethoxy)-6-(1-piperazinyl)pyrazine,
and their pharmacologically acceptable salts and solvates; and
2-(Benzyloxy)-6-(1-piperazinyl)pyrazine,
2-[(2-Methoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-[(3-Methoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-[(3,5-Difluorobenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-(1-Naphthylmethoxy)-6-(1-piperazinyl)pyrazine,
2-(1-Phenylethoxy)-6-(1-piperazinyl)pyrazine,
2-[1-(3-Fluorophenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[1-(2-Methoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-(3,4-Dihydro-2H-chromen-4-yloxy)-6-(1-piperazinyl)pyrazine,
2-(2-Phenylethoxy)-6-(1-piperazinyl)pyrazine,
2-[(2-Phenoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-{[3-(Benzyloxy)benzyl]oxy}-6-(1-piperazinyl)pyrazine,
2-[2-(3-Chlorophenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(2-Methoxyphenyl)ethoxy]-6-(-piperazinyl)pyrazine,
2-[2-(3-Methoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(4-Methoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(2,5-Dimethoxyphenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[(2-Phenylethyl)sulfanyl]-6-(1-piperazinyl)pyrazine,
2-[(5-Fluoro-2-methoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-[(3-Cyanobenzyl)oxy]-6-(1-piperazinyl)pyrazine,
2-[(2-Chlorobenzyl)sulfanyl]-6-(1-piperazinyl)pyrazine,
2-[2-(4-Dimethylaminophenyl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(1H-Indol-3-yl)ethoxy]-6-(1-piperazinyl)pyrazine,
2-[2-(1H-Indol -1-yl)ethoxy]-6-(1-piperazinyl)pyrazine,
4-(Benzyloxy)-2-(1-piperazinyl)pyrimidine,
4-[(2-Methoxybenzyl)oxy]-2-(1-piperazinyl)pyrimidine,
2-{[3-(Benzyloxy)benzyl]oxy}-4-(1-piperazinyl)pyrimidine,
2-Benzyl-6-(1-piperazinyl)pyrazine,
2-[(3,5-Dimethoxybenzyl)oxy]-6-(1-piperazinyl)pyrazine,
1-[6-(Benzyloxy)-2-pyrazinyl]-2-methylpiperazine,
and their pharmacologically acceptable salts and solvates.
As mentioned above, the compounds of the present invention are useful for the treatment (including prophylactic treatment) of serotonin-related disorders, especially 5-HT2c receptor-related, in a human being or in an animal (including e.g. pets), such as eating disorders, especially obesity; memory disorders, such as Alzheimer""s disease; schizophrenia; mood disorders, including, but not restricted to, major depression and bipolar depression, including both mild and manic bipolar disorder, seasonal affective disorder (SAD); anxiety disorders, including situational anxiety, generalized anxiety disorder, primary anxiety disorders (panic disorders, phobias, obsessive-compulsive disorders, and post-traumatic stress disorders), and secondary anxiety disorders (for example anxiety associated with substance abuse); pain; substance abuse; sexual dysfunctions; epilepsy; and urinary disorders, such as urinary incontinence. Additionally, the compounds of the present invention are generally useful in treatment of diseases and disorders of the central nervous system (CNS).
The compounds of the present invention in radiolabelled form, may be used as a diagnostic agent.
This invention relates to methods of making compounds of any formulae herein comprising reacting any one or more of the compounds or formulae delineated herein including any processes delineated herein.
In one aspect, the invention is a method of making a compound of formula (I) delineated herein, taking a compound of the following formula: 
wherein; (i) X and Y represent both nitrogen and Z represents CH, forming a pyrazine derivative, or (ii) X and Z represent both CH and Y represents nitrogen, forming a pyridine derivative, or (iii) X represents Cxe2x80x94CF3, Z represents CH, and Y represents nitrogen, forming a 4-trifluoromethylpyridine derivative, or (iv) Y and Z represent both nitrogen and X represents CH, forming a pyrimidine deriviative, and wherein each Hal is independently a halogen; and reacting the compound with one or more chemical reagents in one or more steps to produce a compound of general formula (I) delineated herein.
The compounds of general formula (I) above may be prepared by, or in analogy with, conventional methods, and especially according to or in analogy with the following methods.
Compounds of formula (I) above in which R1 (or R2 ) are bound to the pyrazine-, pyridine- or pyrimidine ring in (I) via an O, S or N atom in R1 (or R2), are prepared by reacting a compound of the structural formula (III), (IV), (V), or (VI) 
wherein Hal is halogen, with an appropriate amine, alcohol or thiol or its corresponding anion to produce a compound of formula (VII), (VIII), (IX), or (X): 
wherein R1 (or R2) is as defined above and with the proviso that R1 (or R2) is not any of the following groups 
The appropriate alcohol, amine, or thiol may be converted completely or partially to its corresponding anion by treatment with bases, such as triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, K2CO3, NaOH, NaH, KO-t-Bu, lithium diisopropylamide or the like. The reaction is carried out in a solvent, such as dioxane, tetrahydrofuran, tert-butanol or N,N-dimethylformamide (DMF), at 0-200 xc2x0 C. for 1-24 hours. The compound of formula (VII), (VIII), (IX), or (X) is reacted with 1 to 10 molar equivalents of an appropriate amine selected from 
and where R3 and R4 are as defined above, in a solvent such as acetonitrile, dioxane, tetrahydrofuran, n-butanol, DMF, or in a mixture of solvents such as DMF/dioxane, optionally in the presence of a base, such as K2CO3, Na2CO3, Cs2CO3, NaOH, triethylamine, pyridine or the like, at 0-200xc2x0 C. for 1-24 hours to produce the compound of formula (I). When R3 is a nitrogen protecting group as defined above, the subsequent N-deprotection is carried out by conventional methods such as those described in Protective Groups in Organic Synthesis, John Wiley and Sons, 1991 or subsequent editions thereof.
Compounds of formula (I) are prepared by reacting a compound of formula (VII), (VIII), (IX) or (X) above with a 4-hydroxysubstituted piperidine compound of formula (XI) 
wherein R3 is as defined above.
The reaction is carried out in a solvent, such as toluene, DMF, tert-butanol or dioxane, in the presence of a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, KOH, KO-t-Bu, NaH or the like, at 0-200xc2x0 C. for 1-24 hours.
The nitrogen atom in (XI) may be protected with a suitable protecting group, preferably tert-butoxycarbonyl, trityl or benzyl. N-Deprotection is then carried out by conventional methods such as those described in Protective Groups in Organic Synthesis, John Wiley and Sons, 1991 or subsequent editions thereof.
Compounds of formula (I) are prepared by reacting a compound of formula (III), (IV), (V), or (VI) above with an appropriate amine, selected from 
or a 4-hydroxysubstituted piperidine compound (XI) 
and where R3 and R4 are as defined above to produce a compound of formula (XII) or (XIII): 
wherein Hal is as defined above, and X, Y, Z have the same meaning as in formula (I), and Am is an amine residue selected from 
and where R3 and R4 are as defined above. The reaction conditions may be those described for methods A and B above. The compound of formula (XII) or (XIII) is reacted with an appropriate alcohol, amine (other than those defined for Am above) or thiol or its corresponding anions to produce a compound of the formula (I). The reaction conditions may be those described for method A above. When R3 is a nitrogen protecting group as defined above, the subsequent N-deprotection is carried out by conventional methods such as those described in Protective Groups in Organic Synthesis, John Wiley and Sons, 1991 or subsequent editions thereof.
According to another general process (the Suzuki reaction; for a review, see: Chem. Rev. 1995, 95, 2457-2483), the compounds of formula (I) wherein R1 or R2 are aryl or heteroaryl may be prepared by reacting a compound of formula (III), (IV), (V), or (VI) with a boronic acid derivative of the type heteroaryl-B(OH)2 or aryl-B(OH)2, where heteroaryl and aryl are as defined above, in the presence of a transition metal catalyst such as (Ph3P)4Pd, where Ph represents phenyl, in a suitable solvent such as an ether (e.g., 1-2-dimethoxyethane or tetrahydrofuran), in the presence or absence of water, or an aromatic hydrocarbon (e.g., toluene). The reaction is preferably carried out in the presence of a base such as an alkali or alkaline earth metal carbonate (e.g., sodium carbonate) at a suitable temperature up to reflux to provide a compound of formula (XIV) or (XV) 
The compound of formula (XIV) or (XV) is reacted with 1 to 10 molar equivalents of an appropriate amine selected from 
or a 4-hydroxysubstituted piperidine compound (XI) 
to produce a compound of formula (I) and where R3 and R4 are as defined above. The reaction conditions may be those described for methods A and B above.
A compound of formula (XII) or (XIII) is reacted with a boronic acid derivative heteroaryl-B(OH)2 or aryl-B(OH)2 to provide a compound of formula (I). Heteroaryl and aryl are as defined above. The reaction conditions may be those described in method D.
An obtained compound of formula (I) may be converted to another compound of formula (I) by methods well known in the art.
The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are maleic acid, fumaric acid, succinic acid, methanesulfonic acid, acetic acid, oxalic acid, benzoic acid, hydrochloric acid, sulphuric acid, phosphoric acid, and the like.
The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically active (chiral) acids or by chromatographic separation on chiral columns.
The necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds.
In accordance with the present invention, the compounds of formula (I), in the form of free bases or salts with physiologically acceptable acids, can be brought into suitable galenic forms, such as compositions for oral use, for injection, for nasal spray administration or the like, in accordance with accepted pharmaceutical procedures. Such pharmaceutical compositions according to the invention comprise an effective amount of the compounds of formula (I) in association with compatible pharmaceutically acceptable carrier materials, or diluents, as are well known in the art. The carriers may be any inert material, organic or inorganic, suitable for enteral, percutaneous, subcutaneous or parenteral administration, such as: water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such compositions may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like.
The compositions according to the invention can e.g. be made up in solid or liquid form for oral administration, such as tablets, pills, capsules, powders, syrups, elixirs, dispersable granules, cachets, suppositories and the like, in the form of sterile solutions, suspensions or emulsions for parenteral administration, sprays, e.g. a nasal spray, transdermal preparations, e.g. patches, and the like.
As mentioned above, the compounds of the invention may be used for the treatment of serotonin-related disorders in a human being or an animal, such as eating disorders, particularly obesity, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, substance abuse, sexual dysfunctions, epilepsy, and urinary disorders. The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient""s age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.
All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications.
The invention will now be illustrated with the following examples, which however, are for illustrative purposes are not intended to limit the scope of the invention.